There currently is no drug available that stops the progression of Alzheimer's disease (AD). Neurotoxic ?-amyloid peptides (A??) are thought to cause the disease with their accumulation in brain plaques being a hallmark. A? are cleaved from a larger amyloid precursor protein (APP) by proteases, called ?? and ?-secretases. Compounds that inhibit ?-secretase may stop the progression of the disease by reducing the production of A?. CA074Me and loxistatin (also known as E64d or EST) are cysteine protease inhibitors and the cysteine protease, cathepsin B, is a candidate 2-secretase in the regulated secretory pathway. The inhibiton of brain 2-secretase by these compounds is likely due to inhibition of cathepsin B ? -secretase activity. Although loxistatin has been shown safe to use in humans, non-specific binding by this compound, and the structurally similar CA074Me, may limit their therapeutic use. Reversible protease inhibitors offer potential pharmacological advantages as AD therapeutics. This grant, therefore, will develop reversible, small molecule, cathepsin B inhibitors and determine their efficacy in various AD models. Published data show that the reversible peptidomimetic cathepsin B inhibitor, Ac-LVK-CHO, reduces brain A? and brain ?-secretase activity in the guinea pig model, making it likely that the reversible cathepsin B inhibitors developed in this grant will be efficacious. If successful, the work will usher in a new class of AD therapeutics that could have a major impact on treating this dreadful disease. PUBLIC HEALTH RELEVANCE: The relevance of this project to the public health is the development of new and effective Alzheimer's disease drugs. Currently, there is no effective means of stopping the progress of this devastating disease and there is an urgent need for new drugs that do so. This project may result in drugs that halt or, possibly, reverse the progression of AD.